The ultimate goal of this proposal is to utilize a Drosophila model of Dementia with Lewy Bodies (DLB) to gain a better understanding of the molecular and genetic mechanisms that lead to the disease state. DLB is a progressive disorder that is the second most common dementia after Alzheimer's disease, accounting for 17-36% of all dementia cases. Clinically, it is characterized by mental state abnormalities such as cognitive impairment, psychosis and recurrent hallucinations. The pathologic hallmarks of the disease are cytoplasmic inclusions, called Lewy bodies (LB), that are widely distributed throughout paralimbic and neocortical regions and contain alpha-Synuclein. Based on familial inheritance studies, mutations of the alpha-Synuclein gene have been associated with LB formation. Misexpression of alpha-Synuclein in both Drosophila and mice results in neuronal loss and inclusion formation. alpha-Synuclein knockout mice have abnormalities of dopamine release. However, neither the exact function of alpha-Synuclein nor its role in the pathogenesis of DLB have yet been elucidated. We plan to investigate the role of alpha-Synuclein in the pathophysiology of DLB using Drosophila eye as an animal model system. This genetic system is powerful and has been successfully used to study other CNS, disorders such as Huntington's Disease and Spinocerebellar Ataxia. In order to gain a better understanding of mechanisms of pathogenesis of DLB, we propose three Specific Aims: (1) To characterize alpha-Synuclein-induced pathogenesis in the Drosophila eye; (2) To study interactions between alpha-Synuclein and chaperones; (3) To screen for genes that affect alpha-Synuclein-induced pathogenesis. The data we obtain from these experiments should give us a better understanding of the molecular mechanisms that lead to mental dysfunction in DLB. Furthermore, identification of genes involved will lead to new, or effective means of preventing, diagnosing and treatin DLB.